Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep: Role of Dantrolene-Sensitive Aberrant Ryanodine Receptor Calcium Release.
Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep: Role of Dantrolene-Sensitive Aberrant Ryanodine Receptor Calcium Release.
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DOI：
10.1161/circep.117.005659
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
Kalifa J
中科院分区：
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作者：
Avula UMR;Hernandez JJ;Yamazaki M;Valdivia CR;Chu A;Rojas-Pena A;Kaur K;Ramos-Mondragón R;Anumonwo JM;Nattel S;Valdivia HH;Kalifa J
心房缺血/梗死相关的自发性心房颤动（AF）的机制尚未完全阐明。在这里，我们研究自发性房颤的机制在羊模型的左心房心肌梗死（LAMI）。通过结扎冠状动脉左前降支的心房分支创建LAMI。植入ECG回路记录器以监测AF发作。在7只绵羊中，在8天的观察期内体内给予丹曲林（兰尼碱受体阻断剂）（LAMI-D，2.5 mg/kg，IV，BID）。LAMI动物在8天监测期内经历了许多自发性AF发作，这些发作被丹曲林抑制（LAMI，26.1±5.1;假手术，4.3±1.1; LAMI-D，2.8±0.8;每只绵羊的平均值±SEM发作，P<0.01）。光学标测显示自发性局灶性放电（SFD）起源于缺血/正常区边界。SFD是钙驱动的、速率依赖性的，并被异丙肾上腺素增强（0.03 μmol/L，从210±87至3816±1450，SFD/羊），但被丹曲林抑制（至55.8±32.8，SFD/羊，平均值±SEM）。SFD启动AF维持折返转子，通过缺血/正常区边界处的显著传导延迟进行锚定。缺血区心肌细胞NOS 1（NO synthase-1）蛋白表达减少，NADPH（nicotinamide adenine dinucleotide phosphate，reduced form）氧化酶和黄嘌呤氧化酶活性及活性氧（DCF [6-carboxy-2 '，7'-dichlorodihydrofluorescein diacetate]-fluorescence）增加。CaM（钙调蛋白）异常增加[3 H]兰尼碱与缺血区心脏RyR 2（兰尼碱受体）的结合。丹曲林恢复了CaM与RyR 2的生理结合。心房缺血导致绵羊自发性AF发作，由启动折返的SFD引起。缺血区亚硝基氧化还原失衡与强烈的活性氧产生和RyR 2对CaM反应的改变有关。丹曲林给药可使CaM反应正常化，预防LAMI相关SFD和AF发生。这些发现提供了新的见解缺血相关的房性心律失常的机制。
The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI). LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene—a ryanodine receptor blocker—was administered in vivo during the 8-day observation period (LAMI-D, 2.5 mg/kg, IV, BID). LAMI animals experienced numerous spontaneous AF episodes during the 8-day monitoring period that were suppressed by dantrolene (LAMI, 26.1±5.1; sham, 4.3±1.1; LAMI-D, 2.8±0.8; mean±SEM episodes per sheep, P<0.01). Optical mapping showed spontaneous focal discharges (SFDs) originating from the ischemic/normal-zone border. SFDs were calcium driven, rate dependent, and enhanced by isoproterenol (0.03 μmol/L, from 210±87 to 3816±1450, SFDs per sheep) but suppressed by dantrolene (to 55.8±32.8, SFDs per sheep, mean±SEM). SFDs initiated AF-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/ normal-zone border. NOS1 (NO synthase-1) protein expression decreased in ischemic zone myocytes, whereas NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase and xanthine oxidase enzyme activities and reactive oxygen species (DCF [6-carboxy-2’,7’- dichlorodihydrofluorescein diacetate]-fiuorescence) increased. CaM (calmodulin) aberrantly increased [3H]ryanodine binding to cardiac RyR2 (ryanodine receptors) in the ischemic zone. Dantrolene restored the physiological binding of CaM to RyR2. Atrial ischemia causes spontaneous AF episodes in sheep, caused by SFDs that initiate reentry. Nitroso-redox imbalance in the ischemic zone is associated with intense reactive oxygen species production and altered RyR2 responses to CaM. Dantrolene administration normalizes the CaM response, prevents LAMI-related SFDs, and AF initiation. These findings provide novel insights into the mechanisms underlying ischemia-related atrial arrhythmias.